Tahmer Sharkawi

Evaluation of the In Vitro Drug Release from Resorbable Biocompatible Coatings for Vascular Stents

The objective of this work was to prepare a biocompatible and degradable polymer coating for vascular stents that would release a restenosis inhibitor for a sustained period of time. To do so, two film processing techniques were compared using poly(lactic acid) (PLA) and poly(lactic-co-glycolic acid) (PLAGA) polymers as well as the effect of the polymer composition, film thickness and drug loading on the in vitrorelease of dexamethasone from a stent model. Stainless steel square plates (SSSP) were either dipor spraycoated with different polymer proportions of PLA of two different molecular weights (25,000 and 120,000) and PLAGA with a molecular weight of 48,000 with specific drug content and film thickness. The release study was carried out over four months by placing the coated SSSP in a phosphate buffer solution (PBS) pH 7.4. The surface topography of the coated stents was investigated throughout the study by atomic force microscopy (AFM) and differential scanning calorimetry (DSC). Analyses were performed on samples before and after the release study. Dip coating produced a much slower release profile than the spray-coated films. None of the dip-coated SSSP samples achieved a β 50% release in 100 days while most of the spray-coated films released 100% of their load in β 120 days. The polymer composition affected the release profile with the dip-coated film with blended homopolymer films releasing more drug than films composed entirely of one homopolymer; however, this difference was not seen with the spray coated films. Drug loading and film thickness did not show a difference in drug release with the spray-coated films. DSC and AFM results showed progression, with time, in the polymer film degradation and erosion. This study demonstrated that it is feasible to coat a stent model with a biocompatible material and that this coating can release a restenosis inhibitor over time. The release from the biocompatible matrix can be modified by using different processing techniques and the release can be engineered to a desired release profile by blending different molecular weight homopolymers in dip-coated films. On the other hand, spray coating with different molecular weight fractions of the same homopolymer did not produce significant release profiles.

Head-to-Head Comparison of a Drug-Free Early Programmed Dismantling Polylactic Acid Bioresorbable Scaffold and a Metallic Stent in the Porcine Coronary Artery Six-Month Angiography and Optical Coherence Tomographic Follow-up Study

Background—We aimed to evaluate a new drug-free fully bioresorbable lactic acid–based scaffold designed to allow early dismantling synchronized with artery wall healing in comparison with a bare metal stent (BMS). Methods and Results—Twenty-three BMS (3.0×12 mm) and 36 lactic acid–based bioresorbable scaffolds (BRS, 3.0×11 mm) were implanted in porcine coronary arteries. QCA and optical coherence tomographic analyses were performed immediately after implantation and repeated after 1, 3, and 6 months. Microcomputed tomography was used to detect scaffold dismantling. Polymer degradation was evaluated throughout the study. The primary end-point was late lumen loss, and the secondary end-points were scaffold/stent diameter and acute recoil. Acute recoil was low and comparable between the BRS and the BMS groups (4.6±6.7 versus 4.6±5.1%; P=0.98). BRS outer diameter increased significantly from 1 to 6 months indicating late positive scaffold remodeling (P<0.0001), whereas BMS diameter remained constant (P=0.159). Late lumen loss decreased significantly from 1 to 6 months in the BRS group (P=0.003) without significant difference between BRS and BMS groups at 6 months (P=0.68). Microcomputed tomography identified BRS dismantling starting at 3 months, and weight-average molar masses of scaffold parts were 20% and 14% of their initial values at 3 and 6 months. Conclusions—BRS and BMS have similar 6-month outcomes in porcine coronary arteries. Interestingly, BRS dismantling was detected from 3 months and resulted in late lumen enlargement by increased scaffold diameter at 6 months.

Poly(DL-lactic acid) film surface modification with heparin for improving hemocompatibility of blood-contacting bioresorbable devices

This work describes a simple method to immobilize heparin by covalent bonding to the surface of poly(lactic acid) film with the aim of showing improved hemocompatibility. Carboxyl groups present in heparin molecules were activated by reaction with N-hydroxy-succinimide and allowed to react with free amino groups created at the surface of poly(DL-lactic acid) films by controlled aminolysis. Contact angle measurements and XPS analysis confirmed the binding. Quantification was determined by radioactivity using heparin labeled with tritium. The surface exhibited anti factor Xa activity, thus confirming the presence of bounded heparin that kept some biological activity. Finally platelets adhesion showed less platelet adhesion on heparin modified films as well as preserved morphology.

Release behaviour of clozapine matrix pellets based on percolation theory

The release behaviour of clozapine matrix pellets was studied in order to investigate if it is possible to explain it applying the concepts of percolation theory, previously used in the understanding of the release process of inert and hydrophilic matrix tablets. Thirteen batches of pellets with different proportions of clozapine/microcrystalline cellulose (MCC)/hydroxypropylmethyl cellulose (HPMC) and different clozapine particle size fractions were prepared by extrusion-spheronisation and the release profiles were studied. It has been observed that the distance to the excipient (HPMC) percolation threshold is important to control the release rate. Furthermore, the drug percolation threshold has a big influence in these systems. Batches very close to the drug percolation threshold, show a clear effect of the drug particle size in the release rate. However, this effect is much less evident when there is a bigger distance to the drug percolation threshold, so the release behaviour of clozapine matrix pellets is possible to be explained based on the percolation theory.

Compaction behavior and deformation mechanism of directly compressible textured mannitol in a rotary tablet press simulator

Textured mannitol powder is widely used as a pharmaceutical excipient for tablet compaction. In order to choose the right tableting parameters, it is necessary to understand its mechanical behavior during deformation under industrial tableting conditions. The aim of this study was to evaluate the mechanical behavior during deformation of a textured mannitol using a rotary tablet press simulator. Mean yield pressure (Py) obtained by Heckel modeling, Walker coefficients (W) and Stress Rate Sensitivity (SRS) were compared to reference excipients, known for either their plastic (microcrystalline cellulose) or fragmentary (lactose and dibasic calcium phosphate) deformation behavior. Py, W and SRS values showed that the studied textured mannitol has a fragmentary deformation mechanism. Furthermore, this mechanical behavior was not sensitive to lubrication, which is characteristic of fragmentary excipients.

Spray-dried solid dispersions of nifedipine and vinylcaprolactam/vinylacetate/PEG6000 for compacted oral formulations

The aim of this work was to investigate an alternative processing technology for a new polymeric solubilizer used mainly in hot melt extrusion. Poorly soluble nifedipine was co-processed through spray-drying with poly(vinyl caprolactam-co-vinyl acetate-co-ethylene glycol) (PVCVAEG) in different ratios. The resulting spray-dried powders were formulated and compacted into tablets forms. Spray drying produced reduced smooth spherical particles with PVCVAEG and more rough surfaces without PVCVAEG. Crystallinity of the co-processed nifedipine with the polymeric solubilizer was reduced. Plasticization of the polymeric solubilizer was observed with increasing drug content. Diffraction patterns in the small angle region as well as transmission electron microscopy showed results supporting phase separation throughout the spray dried particles of high drug content. Compaction with PVCVAEG improved cohesiveness of spray-dried compacts. Heckel modeling showed that deformation of PVCVAEG containing powders was more plastic compared than brittle nifedipine powders. Dissolution kinetics of all spray-dried samples was improved compared to original nifedipine crystals. Co-processed nifedipine with PVCVAEG did not show improved dissolution rate when compared to spray drying nifedipine alone. All though PVCVAEG is more commonly co-processed with drugs by hot melt extrusion to produce solid dispersions, the results show that it also can be processed by spray drying to produce solid dispersions. PVCVAEG improved compactibility of formulated spray dried powders.

Adjusting a polymer formulation for an optimal bioresorbable stent: a 6-month follow-up study.

AIMS To assess the impact of the composition in L- and D- of lactic acid stereo copolymers without drug elution on the in situ behaviour of prototype stents in terms of biomechanics and biocompatibility. METHODS AND RESULTS PLA50, 75, and 92 stereo-copolymer stents (L/D lactic acid ratio from 1 to 11.5) were processed using the injection moulding facilities of Arterial Remodeling Technologies (Noisy le Roi, France). The resulting 3 mm outer diameter tubes having a diameter at the desired nominal size were laser-cut and crimped on regular angioplasty balloons and chemically sterilised prior to implantation in iliac rabbit arteries. Acute recoil was higher in PLA50 and PLA75 stent-treated arteries than in those with PLA92 stents (17.4 ± 11.4 vs. 13.5 ± 7.6 vs. 4.1 ± 3.8 %, respectively, p=0.001). At one month, in-stent area was higher in PLA92 than in PLA50 and PLA75 stented arteries (5.9 ± 0.6 vs. 1.6 ± 1.6 vs. 2.6 ± 3.2 mm², respectively, p<0.001). Re-endothelialisation was complete, and inflammation was mild around the struts, similar among the three stents. Late lumen loss and neointimal area were low and similar in PLA92 stent-treated arteries one and six months after angioplasty (0.2 ± 0.2 vs. 0.3 ± 0.2 mm, p=0.60; 0.5 ± 0.5 vs. 0.5 ± 0.8 mm², p=0.72, respectively). At six months, inflammation decreased compared to one-month follow-up (1.4 ± 0.5 vs. 0.6 ± 0.5, p=0.006). CONCLUSIONS A stereo-copolymer composition strongly influences biomechanical properties of PLA bioresorbable stents in agreement with what has been known for a long time from other applications, but not biocompatibility. PLA92 stents appeared as presenting acceptable acute deployment and 6-month favourable outcome in the rabbit model despite the absence of drugs.

Predicting the dissolution behavior of pharmaceutical tablets with NIR chemical imaging.

Near infrared chemical imaging (NIRCI) is a common analytical non-destructive technique for the analysis of pharmaceutical tablets. This powerful process analytical technology provides opportunity to chemically understand the sample, and also to determine spatial distribution and size of ingredients in a tablet. NIRCI has been used to link disintegrant, excipients and active pharmaceutical ingredient (API) to tablet dissolution, as disintegrants play an important role in tablet disintegration, resulting in API dissolution. This article describes a specific methodology to predict API dissolution based on disintegrant chemical information obtained with NIRCI. First, several tablet batches with different disintegrant characteristics were produced. Then, NIRCI was successfully used to provide chemical images of pharmaceutical tablets. A PLS regression model successfully predicted dissolution profiles. These results show that NIRCI is a robust and versatile technique for measuring disintegrant properties in tablet formulations and predicting their effects on dissolution profiles. Thus, NIRCI could routinely complement and eventually replace dissolution testing by monitoring a critical material attribute: disintegrant content.

Impact of Physicochemical Environment on the Super Disintegrant Functionality of Cross-Linked Carboxymethyl Sodium Starch: Insight on Formulation Precautions

The aim of this work is to improve the understanding of the physicochemical mechanisms involved in the functionality of cross-linked carboxymethyl sodium starch (CCSS) as a tablet super disintegrant (SD). The behavior and properties of this SD (medium uptake, disintegration times, particle size, and rheology) was investigated in a wetting medium of different physicochemical properties. In particular, the relative permittivity (dielectric constant) of these media was intentionally modified for evaluating its effect on CCSS properties. Results showed different swelling behaviors of CCSS particles according to the relative permittivity of the tested media and allow to propose two underlying mechanisms that explain CCSS functionality. Both the intra-particular swelling and the inter-particular repulsion are affected by the relative permittivity of the media. Finally, disintegration test performed on tablets specially formulated with mannitol (used commonly as an excipient and known to modify relative permittivity) confirmed that the functionality of CCSS and therefore the disintegration of the tablet can be altered according to the mannitol content.

Evaluation of disintegrants functionality for orodispersible mini tablets

Abstract Objective: This work evaluates the functionalities of different superdisintegrants (SD) for manufacturing orodispersible mini tablets (ODMT) by direct compression. Methods: Twenty-three formulations varying in SD type, concentration, and lubricant were used to manufacture ODMT. The ODMT were then characterized for the following properties: friability, porosity, tensile strength, in vivo and in vitro disintegration time (DT). Results: The results show that the presence, type, and concentration of SD did not influence friability, porosity, or tablet tensile strength. With regards to in vivo DT, only cross-linked poly (vinyl pyrrolidone) improved DT in all the tested formulations. Results also showed that when using microcrystalline cellulose (MCC) above 20% in the formulation, DT is longer. Cross-linked carboxymethyl cellulose accelerates DT when the MCC content is less than 20%. As for cross-linked carboxymethyl starch and calcium alginate showed no improvement on DT. Results for in vitro DT were all shorter than in vivo results and there was no correlation with the in vivo evaluation. Conclusions: This study shows that there is a need to develop better in vitro testing that precisely simulates in vivo conditions and that are adapted to ODMT. This standardization of the test methods for ODMTs must be accompanied by an improvement in the comprehension of SD mechanisms.